Technical Field
The present invention relates generally to compositions and methods for treating ischemia. In particular, the present invention relates to the use of stem and/or progenitor cells having enhanced therapeutic properties to treat an ischemic tissue and/or the resulting ischemic tissue damage.
Description of the Related Art
The viability of cells, tissues, and organs in the human body depends on adequate blood flow. Adequate blood flow provides cells with oxygen, glucose, and much needed nutrients that are important for the regulation of cellular physiology and metabolism. Adequate blood flow also allows cell and tissues to respond appropriately to environmental conditions that pose a risk of tissue damage or stress.
Disruption of blood flow to tissues and organs is known as ischemia. Ischemia can be acute or chronic. Both acute and chronic forms of ischemia result in the loss of adequate nutrients to the cells, and if prolonged, will result in hypoxic and/or anoxic conditions. If the ischemia is left untreated, the cells may undergo necrosis or apoptosis, thereby jeopardizing the integrity and health of the tissue or organ.
Ischemia affects millions of patients in the United States each year. Ischemia is caused by a virtually limitless variety of genetic conditions, environmental insults, traumatic injury, or surgical interventions. The most common types of ischemia patients suffer from include, but are not limited to cerebral ischemias, spinal cord injuries, cardiovascular ischemias, limb ischemias, intestinal ischemias, renal ischemias, dermal ischemias (e.g., burns and frostbite wounds) and ischemias resulting from medical and surgical procedures, including, but not limited to organ transplants, and skin grafts.
Cerebral ischemia, referred to as stroke, is the third leading cause of death and the leading cause of serious, long-term disability in the United States (U.S. Centers for Disease Control and Prevention). More than 140,000 people die each year from stroke in the United States. Id. Each year, approximately 795,000 people suffer a stroke. Id. About 600,000 of these are first attacks, and 185,000 are recurrent attacks. Id. Stroke is the interruption or reduction of blood flow in the arteries feeding the brain. When deprived of blood, and thus, oxygen and glucose, brain tissue may undergo ischemic necrosis or infarction. The metabolic events thought to underlie such cell degeneration and death include: energy failure through ATP depletion; cellular acidosis; glutamate release; calcium ion influx; stimulation of membrane phospholipid degradation and subsequent free-fatty-acid accumulation; and free radical generation.
Heart attacks and angina result in myocardial ischemia. 1.5 million heart attacks occur in the United States each year. Id. Almost 14 million Americans have a history of heart attack or angina. Id. More than 500,000 deaths annually can be attributed to heart attacks. Id. A heart attack occurs about every 20 seconds with a heart attack death about every minute. Id. Costs related to heart attack exceed 60 billion dollars per year. Id. Myocardial ischemia occurs when the heart muscle does not receive an adequate blood supply and is thus deprived of necessary levels of oxygen, glucose, and nutrients, resulting in angina, and in many instances, infarction (necrosis) of the myocardial muscle.
Another common cause of myocardial ischemia is atherosclerosis, which is the progressive buildup of plaque—fatty deposits and other cells—in the walls of your arteries that causes blockages in the blood vessels (coronary arteries) that provide blood flow to the heart muscle. Before turning 35, two out of three Americans will have some degree of plaque build-up in their arteries. Heart Disease and Stroke Statistics: 2009 Update. American Heart Association. Jan. 13, 2009. Atherosclerosis is usually a slow and progressive condition that often causes coronary heart disease (CHD)—the leading cause of death in the United States. The total estimated direct and indirect cost of coronary heart disease and stroke in 2009 is $234.3 billion. Id.
Spinal cord injury is the most serious complication of spinal column trauma and also of operations on the aorta for treatment of thoracic and thoracoabdominal aneurysms (Kouchoukos. Thorac. Cardiovasc. Surg. 99:659-664, (1990)). As described in U.S. Pat. No. 5,648,331, the spinal cord is the organ most sensitive to ischemia during cross-clamping of the aorta, where the resultant injury may produce paraparesis or paraplegia. Spinal cord ischemia and paraplegia develop in approximately eleven percent (11%) of patients undergoing elective descending thoracic and thoracoabdominal aneurysm repair and nearly forty percent (40%) undergoing emergent repairs (Crawford. Vas. Surg. 3:389-402, (1986)).
Ischemic events affecting the intestines play a major role of the mortality and morbidity or numerous patients. As described in U.S. Pat. No. 6,191,109, ischemic injury to the small intestine leads to mucosol destruction, bacterial translocation and perforation. The mesenteric arteries supply blood to your small and large intestines. Ischemia occurs when your blood cannot flow through your arteries and your intestines do not receive the necessary oxygen for digestion. Mesenteric ischemia can be acute or chronic and usually involves the small intestine. If left untreated, blockage of the mesenteric arteries may worsen and cause tissues in your intestine to die because they lack enough blood flow.
Critical Limb Ischemia or CLI results from severe obstruction of the arteries, inadequate blood flow or arterial occlusive disease, which seriously decreases blood flow to the extremities (hands, feet and legs) and has progressed to the point of severe pain and even skin ulcers or sores. CLI differs from acute limb ischemia, which generally follows arterial thrombosis or peripheral thromboembolism. Patients with CLI often suffer from severe pain caused by ischemia, tissue loss, ischemic neuropathy, or a combination of these factors. If left untreated, ischemia limbs may become gangrenous and require amputation.
Dermal ischemia results from lack of adequate blood flow to the dermis, and is most often the result of wounding, burns, or frostbite. In burn wounds, the surface tissue necrosis of the initial burn eschar is caused mainly by the heat or chemical insult and is essentially irreversible. Deep and peripheral to the surface tissue necrosis, there is a sizable area of ischemic tissue injury where cells are viable but can easily be further damaged, if left untreated. The area peripheral to and below the ischemic zone is characterized by minimal cell injury but with vasodilatation due to neighboring inflammation-induced mediators is still at risk for ischemia.
Frostbite, once almost exclusively a military problem, is becoming more prevalent among the general population. Research into the pathophysiology has revealed marked similarities in inflammatory processes to those seen in thermal burns and ischemia/reperfusion injury. Although the surgical management of frostbite involves delayed debridement 1 to 3 months after demarcation, recent improvements in radiologic assessment of tissue viability have led to the possibility of earlier surgical intervention. In addition, several adjunctive therapies, including vasodilators, thrombolysis, hyperbaric oxygen, and sympathectomy, are possible.
Currently, resolution of acute and chronic ischemia requires restoration of tissue perfusion and blood flow often using surgical means, which further places patients as risk for ischemic tissue damage. Restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia. Reintroduction of oxygen causes a greater production of damaging free radicals as well as allowing, via removal of the extracellular acidotic conditions, influx of calcium and thus calcium overloading. Overall this results in reperfusion injury which can result in potentially fatal cardiac arrhythmias, also necrosis can be greatly accelerated. Other existing treatments that address ischemic tissue include hyperbaric oxygen, intravenous thrombolytics, anti-inflammatory agents, and local application of angiogenesis promoters. However, these treatments have generally met with limited success, if any.
Accordingly, there is a substantial need in the art for lower risk, more efficient, and longer lasting therapies that treat tissue damage resulting from ischemia and to ameliorate the symptoms associated therewith.